Stress and depression related behaviors incur enormous social and economic costs, and are major leading causes of suicide worldwide. Currently available pharmacotherapies for depression are moderately effective, and that emphasizes the need to further our understanding of the neurobiology of depression and to develop effective pharmacotherapy. Depressive disorder is a complex and multifactorial trait with genetic and environmental contributing factors. Intriguingly, prevalence of depression is greater in women than men. However, the biological basis for this sexual dimorphism is not clearly understood. Recent studies have suggested a potential role for the endocannabinoid (eCB) system in mediating mood and emotional behaviors. However, the role of eCB system in depressive behavior is yet to be clearly understood. In this study, we will determine if there are any gender- specific differences in the components of eCB system associated with depressive behavior using stress (Wistar rat), and genetic (Wistar Kyoto rat) models and in postmortem brains of patients with major depression. We will further evaluate if drugs targeted to eCB system exert antidepressant-like effects in rodent models. The proposed studies would provide new insight/s into the role of eCB system in neurobiology of depression that might assist in the development of effective and personalized pharmacotherapy.